The treatment of cancer-associated thrombosis (CAT) has changed over the last 20 years, going from warfarin up to the early 2000s, through low-molecular-weight-heparin (LMWH) monotherapy and, most recently, to direct oral anticoagulants (DOACs).
To date, LMWH and DOACs are the most commonly used pharmacological anticoagulant agents for CAT .
The main aim of anticoagulation treatment is to reduce recurrent venous thromboembolism (VTE), and DOACs demonstrated a lower risk of recurrent VTE compared with LMWH or warfarin .
In addition, LMWH reduces the risk of recurrent VTE compared to warfarin, even though the incidence of bleeding is comparable .
The latest guidelines recommend monotherapy regimens (e.g., LMWH or DOACs) and combination therapy regimens (e.g., LMWH + DOACs) for the treatment of CAT. LMWH, unfractionated heparin, fondaparinux, rivaroxaban or apixaban can be used for the initial 5–10 days of anticoagulation in cancer patients with acute VTE without severe renal impairment LMWH is preferred over others [4-6].
Secondary benefits of anticoagulation
in addition to reducing recurrent VTE rates, investigators are interested in secondary benefits of anticoagulation, such as survival improvement.
The mortality benefit of LMWH over vitamin K antagonists for CAT treatment has not been established. For this reason, a retrospective cohort analysis measured overall survival (OS) in patients with cancer diagnosed with VTE and treated either with LMWH or warfarin. The Surveillance, Epidemiology and End Results (SEER) and Medicare linked databases were used .
Inclusion criteria were: diagnosis of primary gastric, colorectal, pancreatic, lung, ovarian or brain cancer between 2007 and 2015; qualifying index VTE either contemporaneous with a cancer diagnosis (within 1 month) or at any time after cancer diagnosis; 66 years or older at the time of VTE diagnosis; prescription claims for LMWH or warfarin within 30 days, and survival of at least 14 days, after the index VTE event .
The primary outcome was OS, defined as the time from VTE diagnosis to death from any cause or alive at the time of data cutoff .
In total, 9706 patients were included in the analysis, of which 4853 received LMWH and 4853 received warfarin. The median age was 74 years (66–99 years; interquartile range [IQR]: 70–80 years); 57% were female. The median time from cancer diagnosis to index VTE diagnosis was 3.2 months (IQR: 0.7–10.3 months). The median follow-up was 61 months (range: 0.5–119). The duration of anticoagulants was 136 days in the warfarin group and 65 days in the LMWH group .
Warfarin was associated with significantly improved OS (9.8 months [95% CI: 9.1–10.4]) compared with LMWH (7.2 months [95% CI, 6.8–7.8]), with a hazard ratio (HR) for death of 0.86 [95% CI: 0.83–0.90; p<0.001]. At 90 days, the overall mortality rate was 25% in the warfarin group and 30% in the LMWH group (p<0.001) .
The observed association with improved survival for warfarin over LMWH was consistent across different subgroups, including cancer site, stage, comorbidity burden and age .
Across all cancer stages, warfarin was associated with significantly improved OS compared with LMWH. The observed survival differences were greatest in disease stages one and two, with a median OS nearly 50% longer in the warfarin group (warfarin group: 27.6 months [95% CI: 24.2–30.7 months], LMWH group: 17.1 months [95% CI: 14.7–20.3 months]) .
Median OS in patients with stage four cancers was longer by 1 month in the warfarin group (4.8 months [95% CI: 4.3–5.2] vs 3.8 months [95% CI: 3.5–4.2]) .
In addition, warfarin showed an association with improved survival outcomes greater than LMWH across several different malignancies. For example, gastric and pancreatic cancer had the greatest survival benefits (HR: 0.82, 95% CI: 0.68–0.98 vs HR: 0.82, 95% CI: 0.74–0.90, respectively) .
The warfarin and LMWH groups presented baseline differences, especially in the proportions of pancreatic cancers. However, even after excluding the pancreatic cancer diagnoses, the OS differences remained even .
Should we reconsider warfarin as a treatment for CAT?
First, the results indicate a correlation and not a causation. Also, the study presents some limitations. The study was retrospective; patients were not randomized to warfarin or LMWH and were separated through diagnostic coding. Unknown patient characteristics may have influenced the measured outcome.
Previous analysis failed to demonstrate the role of heparin in reducing mortality at 12 months and 24 months . In addition, a comprehensive systematic literature review of randomized controlled trials showed no statistical difference in mortality reduction between LMWH and warfarin .
Further investigation and prospective trials are necessary to better understand the existence and extent of a difference in survival benefits among the available anticoagulation therapies.
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- Chiasakul T, Redd R, Patell R, et al. Overall survival with warfarin vs. low-molecular-weight heparin in cancer-associated thrombosis. J Thromb Haemost. 2021;19(11):2825-2834.
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